Oncolytic viruses, such as the rabbit-specific myxoma virus (MYXV), represent promising, novel methods to treat patients diagnosed with cancer. While the field of oncolytics has traditionally focused on solid tumors, our recent data demonstrates that the MYXV can also effectively treat the hematopoietic malignancy multiple myeloma. Specifically, MYXV discriminates myeloma cells from normal cells based on differential binding and subsequently eliminates these cells by inducing a rapid apoptotic response. This results in MYXV therapy completely preventing myeloma relapse associated with contamination of autologous transplant samples as well as eradicating residual myeloma in vivo through an apparent immunological mechanism. Unfortunately, the translation of this promising therapy is currently prevented by a lack of understanding concerning the mechanisms involved in treatment. This lack of understanding raises concerns about the accurate prediction of patient responses as well as the potential for treatment to generate adverse events. We therefore put forth the current proposal designed to advance the use of MYXV in a clinical setting by identifying the molecular mechanisms mediating: 1) the induction of an anti-myeloma immune response by systemic MYXV treatment, 2) the mechanisms mediating resistance of myeloma cells to MYXV therapy, and 3) the role that viral binding plays in delivery of MYXV to sites of residual disease. The successful completion of this project could have a significant impact on public health in a variety of ways. First it would advance the use of MYXV as a promising therapeutic for the treatment of patients with myeloma. Additionally, information generated in this proposal might be used to improve treatments with other oncolytic viruses by shedding light on the mechanisms mediating successful in vivo therapy.